Heparin is an anti-coagulant commonly used in some surgical procedures. Heparin is used in high doses in most open-chest heart procedures. The two most common types of open-chest heart procedures are the arrested heart surgical procedure, in which the patient is put on a heart-lung bypass machine, and the beating heart surgical procedure. The heparin significantly reduces clotting or coagulation of the patient's blood.
At the end of a procedure, the normal clotting of the blood is once again desirable. In order to effectively remove the heparin from the patient's blood, protamine is added. The protamine binds to the heparin, deactivating the heparin. The heparin-protamine complex is then cleared from the body by the liver.
It is necessary to determine the amount of heparin in the patient's blood at several points in time. As some patients may have heparin already in their system, an initial determination of the baseline heparin concentration may be required. After heparin is added, the heparin concentration is determined to insure that the heparin has been properly added. While the patient is heparinized, the heparin concentration is monitored to insure that the heparin concentration is maintained above a threshold level. In order to determine the proper amount of protamine to add to deactivate heparin, the concentration of heparin should be determined. After protamine is added, the heparin concentration may again be determined to insure that the heparin has been properly deactivated.
Several methods of determining or inferring heparin concentrations are currently used. In one method, the patient's blood is drawn and sent to a laboratory. In the laboratory, the heparin may be titrated with protamine until the heparin has been entirely bound to protamine. The concentration of heparin may then be determined as a function of the stoichiometry of the protamine titrant used. The stoichiometry of the protamine may be determined by titration against standard heparin samples. The method is far from ideal for use in providing timely feedback to the treating physician, due to the time lag in obtaining results.
A more commonly used method for heparin measurement in the central lab setting is a colorimetric anti-Factor Xa (FXa) assay. This assay is a standard feature on several analyzers and is performed on plasma samples. It uses the principle of heparin-mediated inhibition of FXa. The drawback of this assay is that it needs to be corrected for hematocrit (since it is performed on plasma) as well as the source of heparin (if it is a variable). This assay is more suited for testing high number of samples and is not conducive for testing a few samples. Another significant drawback is a high turnaround time, since this is a central lab test)
In another method, an Activated Clotting Time (ACT) test is used. In this test, the time required for the patient's blood to clot is measured and used to infer a likely heparin level. This method is indirect, and may produce misleading results, as the ACT values may be affected by hemodilution and hypothermia. This method does not directly measure heparin and has limited accuracy.
In still another method, the heparin concentration is localized to a range using multiple protamine samples by using a property of the heparin-protamine interaction. The time required for the heparin and protamine to bind is minimized when the amount of protamine approximates the stoichiometric amount needed to exactly bind the heparin. Insufficient or excess protamine results in longer clotting times. The HEPCON Hemostasis Management System (HMS) available from Medtronic, Inc. (Minneapolis, Minn.) makes use of this property.
The HMS assay system is based on a protamine titration and uses clot formation for end-point detection. The assay is performed in a cartridge containing four to six channels that contain different amounts of protamine as well as dilute thromboplastin (to accelerate clot formation). The end-point of the titration is the detection of clot formation, which is determined by measuring the rate of fall of a plunger mechanism in each cartridge. The channel containing the smallest quantity of protamine that completely neutralizes the heparin exhibits the shortest clotting time. The heparin concentration is measured from the quantity of protamine in that channel (on the basis of the heparin-protamine stoichiometry). Each Hepcon cartridge thus tests a limited range of blood concentrations.
The HMS system can utilize up to 12 different cartridges having differing, known protamine amounts within. The treating physician can estimate the expected range of heparin and select a limited number of cartridges in this range, nominally two from the range of cartridges. A syringe filled with blood is inserted into a machine that injects the blood into the selected cartridge. Clot formation is used for end point detection. Within a few minutes, the cartridge having the proper amount of protamine is automatically indicated, along with a heparin concentration. Use of this device requires the initial correct estimation of heparin, requires a few minutes to run, and has accuracy limited to a discrete range of heparin concentrations based on the resolution of the protamine titration. Numerous cartridges must be stocked if the entire range of possible heparin concentrations is to be measurable. The cartridges have a limited shelf life and must be discarded if not used within the shelf life.
The titration of heparin with protamine has been studied in academic, laboratory settings, but has not resulted in any patient point of care devices that could be used to provide timely heparin concentrations to a treating physician. Several obstacles should be overcome in order to provide the ideal point of care heparin measuring device. A rapid and accurate measurement sensor, an accurate reference or baseline determining system, suitable disposable cartridges, and systems for handling and analyzing all of the above would be desirable and have not yet been developed.